Phenotype Analysis And Genetic Study Of Chinese Treacher Collins Syndrome Patients

Background:Treacher Collins syndrome is a congenital craniofacial disorder which has a high inter-and intra-familial variation in the severity of phenotype.No phenotype-genotype correlation has been discovered yet.So far,it is putative that mutations of TCOF1,POLR1D or POLR1C can lead to insufficient mature ribosomes,activation of ROS and p53 and many other mechanisms which will cause decrease of cranial neural crest cells then result in craniofacial abnormalities.However pathogenic genes still cannot be identified in some cases,what's more,studies in Chinese population are rare.Objective:In this study,we collected clinical details and conducted whole exome sequencing of 8 Chinese TCS patients and 2 normal family members to detect causative mutations and describe the characteristics spectrum observed and causative mutations in TCS individuals of Chinese descent.Furthermore,we aim to understand the relationship between genotype and phenotype,then elaborate the etiology of TCS.Methods:1.Phenotypic analysis:Our cohort included 3 familial and 2 isolated cases from November 2017 to March 2018 which are T3720160105,T3720160105-1,T3720160105-2,T3720170113,T3720170113-1,73720170113-2,T1020180330,T1020180330-2,T2220150810 and T1020160503 respectively.All 8 patients underwent a complete history taking,physical and radiological examination.We analysis these characteristics according to eye,craniofacial skeleton,ear,vertebrate,lower/upper extremities,other organs and intellectual development.2.Genotypic analysis:Blood samples were collected after written informed consent was obtained from the 8 patients and their families.We conduct whole exome sequencing to obtain the causative gene mutation spectrum according to their frequency pathogenic and conservative analysis,then perform PCR to verify them.Define the probable mechanism of these mutations at the molecular level.3.Genotype-Phenotype correlation:Summarize mutation detection results of foreign patients and then compare with Chinese to find out the characteristic of Chinese patients while analyzing the phenotype-genotype correlation.Results:1.The typical fish-like phenotype were observed in all 8 patients.Maxillofacial dysplasia,downslanting palpebral fissures and lower eyelid coloboma were the most common symptoms.There were also some rare symptoms such as malocclusion and rib malformations.Similar to results of international reports,the facial characteristics of Chinese patients were not bilaterally symmetrical and have great variation in the severity among patients.2.Among 8 patients,4 novel pathogenic mutations were identified within the TCOF1 gene which are predicted to lead to premature termination codons resulting in truncated protein:c.1531delC of T3720160105 and his mother?c.537delC of T3720170113 and his father?c.1965₁966insGGGT of T1020180330 and his mother?c.4131₄135del of T2220150810.There was a missense mutation?c.G139A?within POLR1D of T1020160503.3.We observed no phenotype-genotype correlation between the type of gene involved?TCOF1/POLR1D?,the type of mutation in TCOF1,the location of the mutation within TCOF1,family history,and the gender of parental patients.Conclusion:1.These 8 patients could be clinically diagnosed TCS.In addition to typical characteristics,rare symptoms such as malocclusion and rib malformations were also observed.There was no obvious correlation between phenotypes.2.4 novel causative TCOF1 mutation and 1 causative POLR1D missense mutation were detected.We confirmed TCOF1 as the main gene associated with the etiology of TCS in Chinese patients.3.Chinese TCS patients have their own characteristics in clinical phenotype and pathogenesis mutations.